DESCRIPTION: Repeated episodes of ocular HSV-1 lesions can result in irreversible corneal scarring, requiring transplantation to restore vision. Our goals are to define the pharmacological (biochemical and molecular) mechanisms that regulate HSV-1 latency, reactivation, and recurrent disease. Achieving these goals may lead to development of a therapy to block HSV-1 reactivation in patients. The specific aims are: Specific Aim 1: To test the hypothesis that known inducers of HSV-1 reactivation modify the viral nucleosome to induce viral transcription and alter host gene expression. Chromatin immunoprecipitation (ChIP) will be used to assess HSV-1 DNA/histone modifications from latent and reactivated (by drug induction) trigeminal ganglia (TG) from animal models as an assay of transcriptional permissiveness. Latent HSV-1 animals can be induced to reactivate by pharmacological agents, i.e. epinephrine, nicotine, and butyrate (an inhibitor of histone deacetylase). Specific Aim 2: To test the hypothesis that known inhibitors of HSV-1 reactivation alter chromatin remodeling and block transcription. Our hypothesis is that significant changes in chromatin remodeling involve the acetylation of histone tails occurring in the TG during the drug-induced transition from HSV-1 latency to neuronal reactivation. Using a mouse gene array and a newly available rabbit array, we will assess changes in host gene expression due to the drugs listed above that induce HSV-1 reactivation. Bupropion (Zyban and Wellbutrin), celecoxib (Celebrex), and acetylsalicylic acid have been shown to inhibit HSV-1 reactivation in animal models. We will determine whether these inhibitors block chromatin remodeling of promoters in the HSV-1 genome and/or whether the effects occur downstream, for example, by blocking transcription. We will employ host gene expression analysis to determine whether the effects of inhibitors target cellular proteins (mRNAs) or whether they directly target viral processes. The data obtained from the inhibitor and induction studies will be compared, allowing identification of factors controlling HSV-1 reactivation. Our ability to accomplish these aims is enhanced by our extensive experience with the excellent animal models that we have developed. The availability of sensitive and comprehensive host gene expression analysis methods, especially the new rabbit gene array already integrated into our ongoing studies, will aid us in achieving these aims.